Self-Assembling Ability Determines the Activity of Enzyme-Instructed Self-Assembly for Inhibiting Cancer Cells

Abstract

Enzyme-instructed self-assembly (EISA) represents a dynamic continuum of supramolecular nanostructures that selectively inhibits cancer cells via simultaneously targeting multiple hallmark capabilities of cancer, but how to design the small molecules for EISA from the vast molecular space remains an unanswered question. Here we show that the self-assembling ability of small molecules controls the anticancer activity of EISA. Examining the EISA precursor analogues consisting of an N-capped d-tetrapeptide, a phosphotyrosine residue, and a diester or a diamide group, we find that, regardless of the stereochemistry and the regiochemistry of their tetrapeptidic backbones, the anticancer activities of these precursors largely match their self-assembling abilities. Additional mechanistic studies confirm that the assemblies of the small peptide derivatives result in cell death, accompanying significant rearrangement of cytoskeletal proteins and plasma membranes. These results imply that the diester or diamide derivatives of the d-tetrapeptides self-assemble pericellularly, as well as intracellularly, to result in cell death. As the first case to correlate thermodynamic properties (e.g., self-assembling ability) of small molecules with the efficacy of a molecule process against cancer cells, this work provides an important insight for developing a molecular dynamic continuum for potential cancer therapy, as well as understanding the cytotoxicity of pathogenic assemblies.

A Peptide‐Based Supramolecular Hydrogel for Controlled Delivery of Amine Drugs

“…After the synthesis and purification, we found that the peptide Nap‐G D F D F D Y‐CHO was too hydrophobic and could not completely dissolve in aqueous solution by heating or sonication at the concentration of 0.1 wt % (1 mg mL −1 ). Based on previously reported results of using EISA to form hydrogels of hydrophobic peptides, we thus prepared its phosphorylated peptide Nap‐G D F D F D pY‐CHO (Figure A) as a precursor of the possible hydrogelator.…”

“…The LC‐MS traces indicated that there was about 85 % of the precursor being converted to the Nap‐G D F D F D Y‐CHO at the gelling point (4 h, Figure S13). These observations, in combine with our previous examples, further demonstrated that hydrophobic molecules could form hydrogels via hydrolysis processes. To verify the good stability of CHO‐gel in extreme environments, the peptide Nap‐G D F D F D pY‐COOH with a free carboxylic group was used to prepare a control hydrogel (COOH‐gel) using the EISA process.…”

Isothermal kinase-triggered supramolecular assemblies as drug sensitizers

“…Differentiated by the abnormal activities of certain enzymes in cancer cells compared to normal cells, EISA could selectively occur in or around cancer cells and has shown emerging anticancer activities. [11][12][13][14] By targeting the over-expression of secreted or membrane-bound hydrolases (e.g., alkaline phosphatase, MMPs), the extracellular nanober network could block the mass exchange of metabolites in cancer cells. 15 With additional targeting moieties, such as cholesterol or triphenylphosphine (TPP), cancer-specic EISA could further affect the lipid ras 16 or disrupt the normal function of mitochondria.…”

“…17 Moreover, EISA has demonstrated the unique advantage of overcoming drug-resistance issues, 18 which makes it an emerging anticancer strategy. 14,19 Nevertheless, thus far, most of the established EISA approaches share a common strategy in which the enzyme converts hydrophilic precursors to hydrophobic assembly building blocks (e.g., phosphatase catalyzed dephosphorylation) 13,20 and initiates the subsequent self-assembly in situ. As the inverse process of dephosphorylation, the phosphorylation that is naturally mediated by a kinase usually induces the disassembly process.…”

Microenvironment‐Induced In Situ Self‐Assembly of Polymer–Peptide Conjugates That Attack Solid Tumors Deeply

“…[10] The" in vivo self-assembly" strategy, [11] which has attracted tremendous attention in recent years,m ay provide opportunities to meet this challenge.Xuand co-workers have developed nanofibers based on enzyme-instructed self-assembly (EISA) to target cancer cells, [12] overcome multidrug resistance, [13] or induce cell death selectively. [14] However, limited reports confirm the feasibility of this approach in vivo. Polymer-peptide conjugates (PPCs), with long circulation times and good biocompatibility, [15] may provide an ew direction in deep tumor treatment when combined with the in vivo self-assembly strategy.…”